Abstract
BackgroundFatty acid synthase (FASN), the major enzyme in de novo fatty acid synthesis, is highly expressed in breast cancer and its expression is reduced by polyunsaturated fatty acids (PUFAs) in liver. We previously found a positive association between rat mammary tumor levels of the n-6 PUFA arachidonic acid (AA) and tumor weight. We examined the roles of the major n-3 PUFA, docosahexaenoic acid (DHA, 22:6n-3), and the major n-6 PUFA, AA, in FASN expression in, and proliferation of, human breast cancer MCF-7 cells.MethodsThe cells were treated for 48 h with BSA or 60 μM BSA-bound DHA, AA, or oleic acid (OA, 18:1n-9), then were incubated with or without estradiol or insulin. Western blot and 3H–thymidine incorporation assay were used to determine the role of DHA on FASN regulation and MCF-7 cell proliferation.ResultsDHA, but neither AA nor OA, inhibits estradiol-induced and insulin-induced expression of the precursor of sterol regulatory element binding protein-1 (p-SREBP-1), its mature form (m-SREBP-1), and FASN. Estradiol or insulin stimulation increased the pAkt/Akt and pS6/S6 ratios, expression of p-SREBP-1, m-SREBP-1, and FASN, and cell proliferation, and these effects were decreased by DHA. The DHA-induced decrease in FASN expression resulted from reduced pAkt/Akt signaling and not pERK1/2/ERK1/2 signaling. In addition, DHA enhanced the inhibitory effect of LY294002 on pAkt signaling and expression of p-SREBP-1, m-SREBP-1, and FASN. However, addition of rapamycin, an inhibitor of the mTOR signaling pathways, 1 h before addition of estradiol or insulin increased the pAkt/Akt ratio and FASN expression, and this effect was inhibited by addition of DHA 48 h before rapamycin.ConclusionWe conclude that, in MCF-7 cells, DHA inhibits pAKT signaling and thus expression of p-SREBP-1, m-SREBP-1, and FASN and cell proliferation.
Highlights
Fatty acid synthase (FASN), the major enzyme in de novo fatty acid synthesis, is highly expressed in breast cancer and its expression is reduced by polyunsaturated fatty acids (PUFAs) in liver
The cells in Dulbecco’s modified Eagle medium (DMEM) containing 5% fetal bovine serum (FBS) were seeded in dishes or plates for 48 h, the medium was replaced with DMEM containing 1% charcoal/dextran-stripped FBS (CD-FBS) [17] for 24 h, with DMEM containing 5% CD-FBS or FBS supplemented with either vehicle or BSA-bound fatty acid [17] for 48 h, medium, 10 nM estradiol (E2), or 1 μg/ml of insulin was added and the cells incubated for the indicated time
Docosahexaenoic acid (DHA) inhibits E2-induced and insulin-induced expression of Precursor sterol regulatory element-binding protein (p-Sterol regulatory element-binding protein (SREBP))-1, Mature sterol regulatory element-binding protein (m-SREBP)-1, and FASN in MCF-7 cells, but arachidonic acid (AA) and Oleic acid (OA) has no effect Since it has been reported that estradiol increases FASN expression in breast cancer cells and that insulin increases FASN expression in liver [2], we examined whether fatty acids could decrease the estradiol- or insulin-induced increase in FASN expression in MCF-7 breast cancer cells
Summary
Fatty acid synthase (FASN), the major enzyme in de novo fatty acid synthesis, is highly expressed in breast cancer and its expression is reduced by polyunsaturated fatty acids (PUFAs) in liver. FASN expression is undetectable in adult human tissues, but high expression is seen in hormone-sensitive tissues, including lactating breast, endometrial cell proliferation during the menstrual cycle, liver, and adipose tissue, and its expression is regulated by estrogen, progesterone, insulin, and polyunsaturated fatty acids (PUFAs) [1,2,3]. FASN is highly expressed in human epithelial cancers, including breast cancer, prostate cancer, and colon cancer, in which the tumor cells, using the de novo pathway, synthesize most of their own long-chain fatty acids, which are esterified mainly to phospholipids and are incorporated into the cell membrane for cell proliferation [2, 4,5,6]. In MCF-7 human breast cancer cells, SREBP-1c mRNA levels and FASN mRNA levels are high, but SREBP-1a and SREBP-2 mRNA levels are low, and, after addition of epidermal growth factor (EGF), FASN and SREBP-1c mRNA levels are increased, while SREBP1a and SREBP-2 mRNA levels are not [9]
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